Primary nitro compounds oxidation

Nitro compounds are versatile precursors for diverse functionalities. Their conversion into carbonyl compounds by the Nef reaction and into amines by reduction are the most widely used processes in organic synthesis using nitro compounds. In addition, dehydration of primary nitro compounds leads to nitrile oxides, a class of reactive 1,3-dipolar reagents. Nitro compounds are also good precursors for various nitrogen derivatives such as nitriles, oximes, hydroxylamines, and imines. These transformations of nitro compounds are well established and are used routinely in organic synthesis. 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

Nef reaction.4 Nitro compounds, primary or secondary, are converted to tri-alkylsilyl nitronates in greater than 90% yield by reaction with a trialkylsilyl chloride and DBU in CH2C12. The silyl nitronates derived from secondary nitro compounds are oxidized by C1QH4C03H at 25° to ketones in high yield. This sequence is not useful for conversion of primary nitro compounds to aldehydes. 

Nitriles can be obtained in one step by treatment of primary nitro compounds with PC13 and pyridine,420 R may be alkyl or aryl and may contain C=C double bonds or various functional groups. Yields are moderate to good. The reaction has also been carried out with Me3N-S02 and with HMPA.421 Primary azides RCH2N3 have been converted to nitriles RCN with Pd metal.422 Primary nitro compounds RCH2N02 were converted to nitrile oxides 0... 

Nitrile oxide J -I- 2 cycloaddition.1 A key step in a recent stereospecific synthesis of biotin (6) from cycloheptene (1) is an intramolecular [3 + 2]cyclo-addition of a nitrile oxide (a), obtained by dehydration of a primary nitro compound (3), preferably with phenyl isocyanate. This cycloaddilion is more efficient than the well-known olefinic nitrone cycloaddition. The carbon atoms in 6 derived from cycloheptene are marked with asterisks. 

Several methods have been used to convert primary nitro compounds into aldehydes, but the most effective one in the present case is oxidation of the corresponding sodium nitronate with potassium permanganate (1, 950-951). 

Quite independently of Cornforth s efforts, a similar approach was designed and executed by Stevens and coworkers (75JA5940, 76T1599). The isoxazoles were synthesized by one of the three routes outlined in Scheme 25, in which primary nitro compounds are transformed into nitrile oxides by dehydration with either phosphoryl chloride or phenyl isocyanate, or else the same oxides were formed by dehydrogenation with LTA (syn product) or NBS (syn and anti). Reaction of the unstable nitrile oxides in situ with an appropriately substituted alkyne then afforded the isoxazole (294). 

This procedure is illustrative of a general method for preparing a wide range of pure 3,5-disubstituted-4-isoxazole-carboxylic esters and (by hydrolysis) their acids,2 free from positional isomers. A wide range of both primary nitro compounds and of enamino esters can be used,2,3 and the esters thus obtained may then be used as reagents in the isoxazole annela-tion reaction.3,4 The only other general synthesis of these compounds involves chloromethylation and oxidation of a suitable 4-unsubstituted isoxazole.5 This procedure suffers from two difficulties low yields and the unavailability of starting isoxazole. Most methods of isoxazole formation yield a... 

CHN01 - C=0. This transformation can be effected by treatment with base to generate the nitronate anion followed by oxidation with Mo05 Py HMPT. Primary nitro compounds under these conditions are converted to carboxylic acids via an aldehyde. This method is an alternative to the Nef reaction.2... 

Experimental evidences suggest that nitrile oxides are not reaction intermediates and water is released from the nitro compound after reaction with the alkene <07SL2451>. A rationalization of the condensation of primary nitro compounds with alkynes and alkenes under base catalysis has been proposed <07EJO4352>. 

Dehydration of primary nitro compounds (Mukaiyama reaction)12 affords nitrile oxides, which may dimerize to yield furoxans, or otherwise be trapped by suitable dipolarophiles such as double or triple bond systems, leading to the formation of various heterocyclic systems, 5.13 The latter have been used for further derivatization in the heterocyclic series, or in "return" as precursors of acyclic products after ring cleavage,7d-14 for example, 1,3-amino alcohols 6 or (J-hydroxycarbonyl compounds, 9. 

Oxidation. The salt effects rapid cleavage of glycols in high yield. It can be used also for the oxidation of secondary nitro compounds to ketones (Nef reaction).- An excess of the guanidine base is used to form the nitronatc, which is then oxidized to the ketone by the salt. Yields are —80-95%, and are higher than those obtained with iodosylbenzene, C HjIO. Oxidation of primary nitro compounds by his method gives only low to moderate yields of aldehydes. 

Nitrile oxides This acid is an effective catalyst for dehydration of primary nitro compounds (RCH,NO,) to nitrile oxides, which can be trapped with dipolarophiles to form five-membered heterocycles. The reaction is carried out in refluxing mesitylene. 

The Meyer reaction is generally not of rtujor synthetic significarwe. It is observed when a nitro compound is exposed to strong acid. In diis way, carboxylic acids are obtained from primary nitro compounds. The reaction is thought to involve nitrile oxides and hydroxamic acids (RCONHOH) as intermediates. The latter can be isolated by avoiding heat, and the former have been trapped by 1,3-di-polar cycloaddition to alkenes and alkynes. ... 

Because the nitrogen in nitro compounds is at the highest oxidation state, nitro compounds can be oxidized only in the carbon chain to which the nitro group is attached. The oxidation of primary and secondary nitro compounds in the form of their nitronic acids in alkaline medium by potassium permanganate represents a variation of the Nef reaction and gives the same products aldehydes from primary nitro compounds and ketones from secondary nitro compounds (equation 484) [867],... 

The a-hydrogens of nitroalkanes are appreciably acidic due to resonance stabilization of the anion [CH3NO2, 10.2 CH3CH2NO2, 8.5]. The anions derived from nitroalkanes give typical nucleophilic addition reactions with aldehydes (the Henry-Nef tandem reaction). Note that the nitro group can be changed directly to a carbonyl group via the Nef reaction (acidic conditions). Under basic conditions, salts of secondary nitro compounds are converted into ketones by the pyridine-HMPA complex of molybdenum (VI) peroxide. Nitronates from primary nitro compounds yield carboxylic acids since the initially formed aldehyde is rapidly oxidized under the reaction conditions. 

A number of alkyl- and arylnitrile oxides have been reacted with methylenecyclopropane to give 4-oxa-5-azaspiro[2.4]hept-5-enes 1 (4,5-dihydrospiro[isoxazole-5-cyclopropane]). The nitrile oxides were usually generated in situ from the appropriate primary nitro compound with phenyl isocyanate and triethylamine. The addition is usually regioselective in such a way that the oxygen atom forms a bond with Cl of the three-membered ring. 

Yields are 68-84% from salts of primary nitro compounds, and 66-96% from those of secondary nitro compounds. The method can be used with relatively complex nitro compounds. Primary nitro compounds can also be oxidized to carboxylic acids by an excess of permanganate however, to obtain high yields it is advisable to begin the oxidation with only 70-90% of the requisite permanganate and to separate the resulting aldehyde before completing the oxidation. 

Nitrile oxides are conveniently generated in situ by dehydration of primary nitro compounds (with phenylisocyanate or ethyl chloroformate or di-tert-butyl dicarbonate) or from a-chloro-oximes (by treatment with a base). The nitrile oxide reacts with an alkene to form an isoxazoUne or with an alkyne to give a heteroaromatic isoxazole (3.131). Nitrile oxides are prone to undergo dimerization, although this can be minimized by maintaining alow concentration of the dipole in the presence of the dipolarophile. 

Aliphatic nitrile oxides can also be prepared by the dehydration of primary nitro compounds with phenylisocyanate in the presence of a catalytic amount of a tertiary base such as triethylamine. Phenylcarbamate generated in situ on reaction with phenylisocyanate is subsequently converted into urea derivative (Scheme 5.37). 

SCHEME 5.37 Generation of nitrile oxides from primary nitro compounds. 

In 1960 a new access to nitrile oxides was provided by dehydration of primary nitro compounds 4, achieved with 2 equiv of phenyl isocyanate, which is converted into diphenylurea, beside the substituted furoxan isoxazole derivatives are obtained in the presence of suitable dipolarophiles (Scheme 8.1) [6,7]. This method for the synthesis of isoxazoles has become popular in turn and both methods have been widely employed over the past 50 years the subject has been repeatedly reviewed [8-15]. 

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